Process for formulation of carbapenem antibiotic compositions

A process for converting a carbapenem compound of formula I:

• into a carbapenem compound of formula II:
• comprising the steps of:
• a. preparing a solution of from about 1 to about 3N of sodium hydroxide and chilling the solution to a temperature of from about 0° to about 10° C.;
• b. charging a total of from about 40 to about 60% by wt., based on 100% by wt. total of the batch weight of Water for Injection exhibiting a temperature of from about 20 to about 85° C. into a compounder having means for mixing, and cooling the water to a temperature of from about 0° C. to about 5° C.;
• c. charging sufficient carbonate selected from sodium bicarbonate, sodium carbonate and mixtures thereof, into the compounder to prepare a final formulation exhibiting 1 mole equivalent of carbonate/active carbapenem, dissolving the same, and maintaining the solution at a temperature range of from about 0° to about 5° C. to prepare a carbonate solution;
• d. maintaining the carbonate solution at a pH of from about 7.5 to about 9.0, and a temperature of about 0° to about 5° C.;
• e. thawing a sufficient amount of bulk carbapenem of formula I to provide a formulation exhibiting a concentration of about 200 g/l from a temperature of about −20° C. to about temperature of from about 5 to about 25° C., and slowly charging the same into the compounder with mixing of the carbonate solution to completely dissolve the bulk compound, while maintaining the compounder temperature of from about 0° to about 5° C. to produce an active carbapenem solution;
• f. adding the sodium hydroxide solution to the active carbapenem, as required during step e., and maintaining a pH of from about 7.0 to about 8.0;
• g. adjusting the active carbapenem solution to 95% by weight of the final product weight, based on 100 total weight percent, utilizing water for injection, as required and maintaining the bulk carbapenem of formula I solution in a temperature of from about 0° to about 5° C.;
• h. adding the sodium hydroxide solution to the bulk carbapenem of formula I solution to maintain a pH of from about 7.2 to about 7.8;
• i. adding Water for Injection, as required, to adjust the active carbapenem solution to q.s. of 100% by wt., based 100% by wt. total weight, and maintaining a temperature of from about 0 to about 5° C.;
• j. sealing and pressurizing the compounder containing the bulk compound of formula I solution to about 15 psig to initiate filtration;
• k. filtering the bulk compound of formula I solution through a sterilizing filter into a continuously cooled, sterile, receiving vessel exhibiting a temperature of from about 0° to about 5° C. producing a final sterile beta-lactam carbapenem formulation;
• and
• l. aseptically filling the final sterile beta-lactam carbapenem formulation into sterile glass vials, and partially sealing the vials with dry, sterilized, lyophilization stoppers;
• m. lyophilizing the formulation by freezing in the glass vials at a temperature of from about −45° to about −40° C. to produce a frozen formulation;
• n. primary drying the frozen formulation at a temperature of from about −25° to about −15° C. for about 48 to 60 hours at a pressure of about 80 mTorr;
• o. secondary drying the formulation at a temperature of from about 40° to about 60° C. at a pressure of about 80 mTorr or lower for a time period of from about 3 to about 10 hours;
• p. cooling the vials to ambient temperature;
• and
• q. sealing the vials under a partial vacuum of about 0.9 bar/700 Torr or lower, while maintaining a temperature of about 25° C.,
• wherein the final sterilized beta-lactam carbapenem antibiotic formulation of formula II exhibits a carbapenem concentration of about 200 g/l and a carbonate content of about 1 mole equivalent.